1. Field of the Invention
The present invention relates generally to the field of drug abuse and addiction therapy. More specifically, the present invent ion relates to the generation and use of high affinity monoclonal antibodies (MAb) and their derivatives as long acting stimulant antagonists for treating the medical problems associated with drug abuse and addiction. In addition, the antigen binding fragments (Fab) and other small molecular fragments of these monoclonal antibodies can serve as a shorter acting stimulant antagonist for treating medical problems like drug overdose.
2. Description of the Related Art
Knowledge gained from basic research into the neurobiology of drug abuse has led to major discoveries in medicine. Nevertheless, the development of medical strategies for treating the complex array of neurological problems associated with drug abuse has been frustratingly slow. In particular, development of medical treatments for alleviating the adverse psychosocial and health effects of d-methamphetamine and similar stimulants is badly needed.
d-Methamphetamine-related hospital emergency cases across the U.S. increased 256% from 1991 to 1994 (1). The 1995 Toxic Exposure Surveillance System data showed there were 7,601 people treated in health care facilities for amphetamine-like drugs and other stimulants. This is particularly striking since during the same period there were only 3,440 cases of cocaine treatment and a total of 5,170 cases of all types of legal and illegal narcotics (including morphine, codeine and heroin). The current rise in d-methamphetamine use is also alarming because, unlike cocaine, it does not have to be imported. Even an amateur chemist can synthesize this drug in his home using easily obtained reagents and equipment.
The adverse clinical effects from d-methamphetamine include hypertension, tachycardia, dysrhythmias, sleep deprivation, a stimulant-induced psychosis as well as hyperlocomotion and stereotyped behavior (2). The central nervous system (CNS) actions of d-methamphetamine result from its effects on several CNS neurotransmitter systems, ion channels, and presynaptic catecholamine uptake systems. In particular, d-methamphetamine has profound effects on the CNS dopaminergic system, where d-methamphetamine acts as a substrate for the dopamine transporter and causes dopamine to be transported extraneuronally which increases synaptic concentrations of dopamine (2). Indeed, d-methamphetamine can be transported into the presynaptic terminal without inhibiting reuptake of the neurotransmitter into the presynaptic terminal. These dopaminergic effects are associated with mood changes, excitation, motor movements and regulation of appetite.
There are no specific treatments (either as antagonists or as agonist replacement therapies) currently available for d-methamphetamine abuse. Therapy for drug overdose only involves medical management of the symptoms (e.g. hyperactivity, psychosis, and increased core body temperature) with palliative care until the drug effects subside, whereas therapy for helping patients gain control of their addiction mostly involves long term behavioral modification therapy and counseling without any significant useful medications.
One biologically based approach to treating drug overdose is the use of high-affinity, drug-specific Fab fragments of antibodies or intact IgG. In addition to being relatively safe, except for occasional allergic reactions that can be prevented by the use of human monoclonal antibodies, antibody-based therapies act as pharmacokinetic antagonists which gives them several important advantages over treatment with more conventional receptor antagonists. Firstly, there is no receptor antagonist for d-methamphetamine effects at any of its sites of action in the CNS. One of the limitations of development of receptor antagonists is that they will only be capable of attenuating the effects at one type of receptor. Most drugs of abuse have multiple sites of action. Secondly, unlike conventional receptor antagonists (or agonists), antibodies do not inhibit the actions of normal endogenous ligands. In fact, it could be argued that removal of the drug by antibodies might allow for a more normal recovery than treatment with a chemically-derived small molecule competitive agonist or antagonist. Thirdly, since antibodies (and their derivatives like Fab) have extremely high affinities and do not cross the blood-brain barrier, they actually lower drug concentrations throughout the CNS (3). This allows for a rapid, neuroprotective effect at all sites of action in the CNS.
The prior art is deficient in the lack of effective means of treating d-methamphetamine overdose and addiction. The present invention fulfills this long-standing need and desire in the art.
The present invention is drawn to the generation of high affinity monoclonal antibodies, and the use of intact and smaller derivatives of the antibody for treating the medical problems associated with stimulant drug abuse. D-Methamphetamine is the prototypic amphetamine-like drug molecule since it has severe addiction liability, and repeated use of the drug can lead to life-threatening cardiovascular problems, severe depression, psychosis, violent behavior and significant criminal activity. The antibodies are specifically designed to recognize the unique and/or common molecular features of several dangerous stimulant and hallucinogenic drugs of abuse and their psychoactive metabolites, e.g., d-methamphetamine, d-amphetamine, (+/xe2x88x92) 3,4-methylenedioxymethamphetamine (MDMA), and (+/xe2x88x92) 3,4-methylenedioxyamphetamine (MDA) or structually related stimulants and/or hallucinogenic analogs.
In one embodiment of the present invention, there is provided a method to generate antibodies that are specifically designed to recognize the common molecular features of several dangerous stimulant and hallucinogenic drugs of abuse and their psychoactive metabolites chosen from the representative group consisting of d-methamphetamine, (+/xe2x88x92) 3,4-methylenedioxymethamphetamine, d-amphetamine, and (+/xe2x88x92) 3,4-methylenedioxyamphetamine or structually related stimulants and/or hallucinogenic analogs.
In another embodiment of the present invention, there is provided a series of haptens designed for generating class-specific monoclonal antibody that could be used as a pharmacokinetic antagonist for treating the medical problems associated with methamphetamine-like stimulants. There is also provided compounds used in coupling the hapten to a protein for generating the class-specific monoclonal antibody.
In another embodiment of the present invention, there is provided a method to directly compare active and passive immunization as treatments for d-methamphetamine addiction in rats.
In yet another embodiment of the present invention, there is provided a method to study the effect of anti-d-methamphetamine Fab on pharmacokinetics and behavior after stimulant-induced toxicity in rats.
In still yet another embodiment of the present invention, there is provided a method of antibody treatment in a preclinical model of human drug overdose.
In another aspect of the present invention, there is provided a method to assess d-methamphetamine self-administration in rats as a measure of the therapy""s ability to reduce drug addiction liability.
The present invention is further drawn to a method to study the effect of antibody-based therapy on d-methamphetamine toxicity in dogs or primates.
Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure.